Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease of unknown origin. Although epidemiology has served to identify both genetic and environmental candidates, no definitive causal factor(s) for neurodegenerative diseases has been found. ALS-parkinsonism-dementia complex (ALS-PDC) of Guam has been historically and experimentally associated with the consumption of seeds of the cycad palm known to contain various cyto- as well as specific neurotoxins. We have recently developed a model of ALS-PDC in which mice fed washed cycad seed flour develop the full spectrum of behavioral and pathological outcomes of the disease, including losses of motor neurons in spinal cord and motor cortex along with significant and progressive diminutions in motor function. In vitro studies have identified the putative neurotoxins in washed cycad flour as variant forms of sterol glucosides. We hypothesize that sterol glucosides similar to those found in cycad and other plants, or those made by specific bacteria may play a causal role in the events leading to motor neuron degeneration in the various forms of ALS. Our working hypothesis is that sterol glucosides induce a region-specific and progressive pattern of neuronal death that can be attenuated by anti-excitotoxic, antioxidant or antiapoptotic agents. This hypothesis will be tested in in vivo and in vitro experiments in which the mechanisms by which sterol glucosides induce neuronal degeneration will be explored. With our in vivo experiments, we will assess the effects of sterol glucosides on the pattern of protein expression in brain areas and determine the time points of maximum neurotoxic effect. The aim of the in vitro experiments is to characterize the lethal effects of various related sterol glucosides on neuronal cells, for which the neurotoxicity of a serial dilution of this compound will be assessed. We will also attempt to determine which death pathways are involved in the presumed effects and test the potential of specific pharmacological agents to prevent the neuronal loss induced by sterol glucoside. In addition, we will assess whether sterol glucosides or their metabolites are present in higher levels in the blood of ALS patients. Our long-term Aims are to identify the causative molecule(s) in ALS-PDC which can share common basis with the rest of the neurodegenerative diseases. [unreadable] [unreadable] [unreadable]